Substituted di-t-butylphenols

ABSTRACT

Novel compounds which are 2,6-di-t-butylphenols substituted on the 4 position by an anilino group, which anilino group is substituted by a carboxyl substituent, a tetrazolyl substituent or an N-methyltetrazolyl substituent, are useful antiallergic agents. Pharmaceutical compositions containing and pharmacological methods of using such compounds are also disclosed, as are synthetic intermediates for preparing such compounds. Certain of the synthetic intermediates also exhibit useful antiallergic activity.

CROSS-REFERENCE TO RELATED APPLICATION

This application is continuation-in-part of pending application U.S.Ser. No. 757,358, filed Jul. 22, 1985.

TECHNICAL FIELD

This invention relates to substituted di-t-butylphenols which areanti-allergic agents. Pharmaceutical compositions containing suchcompounds, pharmacological methods for using such compounds andsynthetic intermediates for preparing such compounds are also disclosed.

BACKGROUND OF THE INVENTION

The leukotrienes are a group of biologically active mediators derivedfrom arachidonic acid through the action of lipoxygenase enzyme systems.There are two groups of leukotrienes derived from the common unstableprecursor Leukotriene A₄. The first of these are the peptido-lipidleukotrienes, the most important being Leukotrienes C₄ and D₄. Thesecompounds collectively account for the biologically active materialknown as the slow reacting substance of anaphylaxis.

The leukotrienes are potent smooth muscle contracting agents,particularly on respiratory smooth muscle, but also on other tissues aswell. In addition, they promote mucous production, modulate vascularpermeability changes and are potent inflammatory mediators in humanskin. The most important compound in the second group of leukotrienes,namely dihydroxy fatty acids, is Leukotriene B₄. This compound is apotent chemotactic agent for neutrophils and eosinophils and, inaddition, may modulate a number of other functions of these cells. alsoaffects other cell types such as lymphocytes and, for example, maymodulate the action of suppressor cells and natural killer cells. Wheninjected in vivo, in addition to promoting the accumulation ofleukocytes, Leukotriene B₄ is also a potent hyperalgesic agent and canmodulate vascular permeability changes through a neutrophil dependentmechanism. Both groups of leukotrienes are formed following oxygenationof arachidonic acid through the action of a lipoxygenase enzyme. See,for example, D. M. Bailey et al., Ann. Rpts. Med. Chem., 17, 203 (1982).

RESPIRATORY CONDITIONS

Asthma. The leukotrienes are potent spasmogens of human trachea,bronchus, and lung parenchyma, and when administered to normalvolunteers as aerosols are 3,800 times more potent than histamine atinducing a 50% decrease in air flow at 30% of vital capacity. Theymediate increases in vascular permeability in animals and promote mucousproduction in human bronchial explants. In addition, Leukotriene B₄ mayalso mediate mucous production and could be an important mediator ofneutrophil and eosinophil accumulation in asthmatic lungs. Lipoxygenaseproducts are also thought to be regulators of mast cell degranulation,and recent studies with human lung mast cells have suggested thatlipoxygenase inhibitors (but not corticosteroids), may suppressantigen-induced mast cell degranulation. In vitro studies have shownthat antigen challenge of human lung results in the release ofleukotrienes and that, in addition, purified human mast cells canproduce substantial amounts of leukotrienes. There is, therefore goodevidence that the leukotrienes are important mediators of human asthma.Lipoxygenase inhibitors would, therefore be a new class of drugs for thetreatment of asthma. See, for example, B. Samuelsson, Science, 220,568-575 (1983).

SKIN DISEASES

Psoriasis. Psoriasis is a human skin disease which affects between twoand six percent of the population. There is no adequate therapy forpsoriasis and related skin conditions. The evidence for leukotrieneinvolvement in these diseases is as follows. One of the earliest eventsin the development of prepapillary lesions is the recruitment ofleukocytes to the skin site. Injection of Leukotriene B₄ into human skinresults in a pronounced neutrophil accumulation. There are grossabnormalities in arachidonic acid metabolism in human psoriatic skin. Inparticular, highly elevated levels of free arachidonic acid can bemeasured as well as large amounts of lipoxygenase products. LeukotrieneB₄ has been detected in psoriatic lesions, but not in non-involved skin,in biologically significant amounts.

ALLERGIC CONDITIONS

Leukotrienes can be measured in nasal washings from patients withallergic rhinitis and are greatly elevated following antigen challenge.Leukotrienes may mediate this disease through their ability to regulatemast cell degranulation, to modulate mucous production and mucocillaryclearance, and to mediate the accumulation of inflammatory leukocytes.

Leukotrienes may also mediate other diseases. These include atopicdermatitis, gouty arthritis, gall bladder spasms and ulcerative coliris.In addition, they may have a role in cardiovascular disease becauseLeukotrienes C₄ and D₄ act as coronary and cerebral arterialvasoconstrictors and these compounds may also have negative inotropiceffects on the myocardium. In addition, the leukotrienes are importantmediators of inflammatory disease through their ability to modulateleukocyte and lymphocyte function.

Many substituted di-t-butylphenols are known. Generally these compoundsmay be useful as antioxidants. Some of these compounds are also known tobe active antiinflammatory agents.

Compounds wherein 2,6-di-t-butylphenol is substituted in the 4 positionby an unsubstituted phenyl or certain simply-substituted phenyls areknown antiinflammatory agents. See, for example, U.S. Pat. No. 4,172,151and references cited therein. The compound2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexandiene-1-oneis disclosed in Chemical Abstracts 67:81701n.

No compounds wherein a 2,6-di-t-butylphenol is substituted in the 4position by an anilino group wherein such anilino group is substitutedby a moiety including carboxy, tetrazolyl, N-methyl-tetrazolyl, orN-trifluoromethylsulfonyl are known.

SUMMARY OF THE INVENTION

This invention relates to certain di-t-butylphenols containing ananilino group which contain carboxy, tetrazolyl, N-methyltetrazolyl, orN-trifluoromethylsulfonyl. These compounds are useful as inhibitors ofmammalian leukotriene biosynthesis. As such, these compounds are usefultherapeutic agents for treating allergic conditions, particularlyasthma. Pharmaceutical compositions comprising such compounds,pharmacological methods of using such compounds, and syntheticintermediates for preparing such compounds are also described. Certainof the synthetic intermediates also exhibit useful pharmacologicalactivity as antiallergic agents.

Certain compounds of the invention are also useful as syntheticintermediates for preparing certain of the antiallergic compounds whichare disclosed and claimed in U.S. Ser. No. 06/879,472, filed of evendate and commonly assigned, incorporated herein by reference. Moreover,it is believed that certain of the antiallergic compounds disclosed insaid copending application are prodrugs of certain antiallergiccompounds disclosed herein. For example,N-(3-carboxyphenyl)-N-(3,5-di-t-butyl-4-hydroxyphenyl)succinamic aciddisclosed in said copending application is believed to possibly be aprodrug of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid which isdisclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of Formula I: ##STR1##wherein R is hydrogen, lower alkyl, lower alkoxy, lower alkylthio,halogen (preferably chloro or fluoro), amino, lower alkylamino,di(lower)alkylamino, lower acylamido or hydroxy, and n is 0, 1 or 2 withthe proviso that if n is 2, then all R substituents combined contain nomore than 6 carbon atoms; R' is hydrogen, lower alkyl, acetyl ortrifluoroacetyl; A is carboxyl, tetrazolyl, N-methyltetrazolyl or##STR2## and when A is carboxyl, B is a carbon-carbon bond, loweralkylene, lower alkenylene, lower alkylene containing one ether orthioether link in the alkylene chain, or ##STR3## when A is tetrazolylor N-methyltetrazolyl, B is a carbon-carbon bond, --CH₂ -- or ##STR4##and when A is ##STR5## B is a carbon-carbon bond; and derivatives ofcompounds wherein A is carboxyl selected from the group consisting ofthe lower alkyl esters, (lower)alkylamino(lower)alkyl esters,pharmaceutically acceptable (lower)alkylamino(lower)alkyl esteracid-addition salts and pharmaceutically acceptable carboxylate salts,and derivatives of compounds wherein B is tetrazolyl selected frompharmaceutically acceptable alkali metal and alkaline earth salts of thetetrazolyl moiety.

Presently preferred are compounds wherein the group --B--COOH,--B-tetrazolyl or --B-N-methyltetrazolyl is oriented para or meta to the##STR6## linking group.

Presently preferred compounds are those wherein A is carboxyl.

Presently preferred as B is a carbon-carbon bond. When B is alkylene itis preferably methylene. When B is alkenylene it is preferablyethenylene.

When R is lower alkyl, lower alkoxy or lower alkylthio, it is presentlypreferred to be methyl, methoxy, or methylthio respectively. Thepresently preferred R group is hydrogen.

By "lower" as used in connection with "alkyl" and "alkylene" is meantthat such groups contain one to about four carbon atoms. Most preferredalkyl groups contain one or two carbon atoms. By "lower" as used inconnection with "alkenylene" is meant that such groups contain two toabout four carbon atoms.

In the compounds of Formula I wherein A is tetrazolyl, two tautomericforms of tetrazolyl exist as is known to those skilled in the art.Tautomerism does not exist in tetrazolyl moieties where the tetrazolylring is substituted on a nitrogen atom by methyl. Instead, two N-methylisomers are obtained, one in which the methyl group is in the1-position, the other in which it is in the 2-position. All suchtautomers and isomers are within the scope of this invention.

It is well known to the art that pharmaceutically acceptable salts suchas alkali metal, alkaline earth, aluminum and other metal and aminesalts of pharmaceutically active acids are the equivalents of the acidsin terms of activity, and in some cases may even offer advantages inabsorption, formulation and the like. Pharmaceutically-acceptablecarboxylate salts of the compounds of the invention which containcarboxyl as A are prepared in an inert atmosphere by reaction of theacid with a base and subsequent evaporation to dryness, preferably undermild conditions. The base may be organic, e.g., sodium methoxide or anamine, or inorganic, e.g., sodium hydroxide. Alternatively, the cationof a carboxylate salt, e.g., sodium, may be displaced by a second cationsuch as calcium or magnesium when the salt of the second cation is moreinsoluble in a selected solvent.

Other useful derivatives of the compounds of the invention which containcarboxyl as A include alkyl esters, alkylaminoalkyl esters, and salts ofthe latter. In the ester derivatives, the hydrogen portion of thecarboxylic acid group is replaced with an alkyl or substituted alkyl,preferably an alkylaminoalkyl group.

Esters of the compounds of the invention may be obtained asintermediates during the preparation of the acidic compound. In somecases, the esters may be prepared directly using standard syntheticmethods. These esters may exhibit antiallergic activity, but they areprimarily of interest as synthetic intermediates, although in someinstances hydrolyzable or salt-forming esters may be of interest astherapeutic agents. Preferred esters are alkyl esters andalkylaminoalkyl esters having one to four carbon atoms in the alkylgroup. Especially preferred are alkylaminoalkyl esters such as thedimethylaminoethyl esters which will form salts, e.g., hydrochlorides.

Ester derivatives may be obtained by alkylation of an alkali metal saltof the compound in dimethylformamide with an alkyl iodide ordialkylaminoalkylchloride, or by starting with esters instead of acidsin Scheme I, Step (1) below.

Pharmaceutically acceptable alkali metal and alkaline earth salts mayalso be prepared of compounds of Formula I wherein A is tetrazolyl bymethods known to those skilled in the art.

The preferred compounds of Formula I are4-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid,3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid,5-[3-(3,5-di-tertiary-butyl-4-hydroxyanilino)phenyl]tetrazole, and5-[4-(3,5-di-tertiary-butyl-4-hydroxyanilino)phenyl]tetrazole.

Compounds of the invention may be prepared by the method of Scheme I,wherein A, R, and B are as defined above, and R' is hydrogen. ##STR7##

The reaction of step (1) is a Lewis acid catalyzed condensation of theknown compound 2,6-di(tertiary-butyl)-p-benzoquinone (II) and asubstituted aromatic amine (III). Suitable substituted aromatic aminesfor preparing compounds of Formula I wherein A is carboxyl are knowncompounds such as the aminobenzoic acids, for example, 3- and4-aminobenzoic acid, the aminophenylacetic acids, aminophenylbutyricacids, aminophenylthioacetic acids, aminophenyloxyacetic acids, alkylaminophenylacetates, aminophenylcinnamic acids, and the like. Similarly,suitable tetrazolyl-substituted aromatic amines for providing compoundsof Formula I wherein A is tetrazolyl are known such as 5-(3or4-aminophenyl)tetrazoles.

Suitable Lewis acid catalysts include boron trifluoride, tintetrachloride, titanium tetrachloride and the like.

The reaction of step (1) is carried out by combining the reactants in aninert solvent such as an ether, for example, tetrahydrofuran, andheating gently, if necessary. The products of Formula IV are novelsolids which are readily isolated and may be recrystallized from polarsolvents.

The reaction of step (2) is a reduction of the imino quinone system ofthe intermediate of Formula IV to an amino phenol. It is readilyaccomplished using catalytic reduction with hydrogen gas in an inertsolvent when A is carboxyl. It may be carried out under neutralconditions or in the presence of base, for example, an equimolar amountof base. Suitable catalysts include platinum or palladium on charcoal.Chemical reduction can also be carried out, for example, with sodiumthiosulfite, or zinc and acetic acid to provide compounds wherein A iscarboxyl or tetrazolyl. Chemical reduction is preferred when B containsa double bond.

Compounds of the invention wherein R' is alkyl and A is carboxy areprepared from a compound of Formula V (obtained above) by reacting thecompound with an alkyl halide, particularly an alkyl bromide or an alkyliodide. This reaction may be carried out in a solvent such asN,N-dimethylformamide, optionally in the presence of base. When base ispresent, the carboxyl will generally become esterified, and thereforesubsequent hydrolysis by conventional methods may be desired.

Compounds of the invention wherein R' is acetyl or trifluoroacetyl and Ais carboxy are prepared from a compound of Formula V by reacting thecompound with the appropriate anhydride.

Compounds of Formula I wherein A is N-methyltetrazolyl are preferablyprepared by alkylating an alkali metal salt of the correspondingcompound of Formula I wherein A is tetrazolyl with methyl iodide.

Compounds of Formula IV wherein A is ##STR8## may be prepared from thecorresponding compound of Formula IV wherein A is carboxy via reactionof that compound with thionyl chloride and subsequent reaction of theresulting acid chloride with sodium trifluoromethanesulfonamide.Catalytic reduction provides compounds of Formula I wherein A is##STR9##

Compounds of Formula I wherein A is tetrazolyl may also be prepared bythe method of Scheme II wherein R, n and B are as defined above and R'is hydrogen. ##STR10##

The reaction of step (1) of Scheme II is a Lewis acid catalyzedcondensation similar to step (1) of Scheme I except that here anaminonitrile of Formula VI is used in place of the substituted aromaticamine used in step (1) of Scheme I. Compounds of Formula VI are known ormay be prepared by conventional methods. The reaction is conducted asdescribed in connection with step (1) of Scheme I. The product of step(1) of Scheme II is a novel intermediate of Formula VII.

The reaction of step (2) of Scheme II is a reduction of the type (andperformed using the method of) step (2) of Scheme I to provide a novelintermediate of Formula VIII.

In step (3), the intermediate of Formula VIII is reacted with sodiumazide in the presence of ammonium chloride and lithium chloride. Thereaction is preferably conducted in N,N-dimethylformamide and isconducted under a nitrogen atmosphere and accompanied by heating.

In step (4), the intermediate of formula VIII is hydrolyzed, in an inertatmosphere, by known means such as with sodium hydroxide in aqueousethanol, to provide compounds of Formula X.

Compounds of the invention wherein R' is alkyl and A is carboxy,tetrazolyl or N-methyltetrazolyl may be prepared by alkylating theintermediate of Formula VIII by conventional methods prior to conductingstep (3) or (4).

Again, as in Scheme 1, compounds of the invention wherein R' is acetylor trifluoroacetyl may be prepared from the compounds of Formula IX andX by reacting the compound with an appropriate anhydride as discussedpreviously.

Similarly, N-methyltetrazolyl derivatives may be prepared as describedin connection with Scheme I above.

The anti-allergic activity of the compounds of Formula I may bedemonstrated via a variety of biological assays including in vitroassays for measuring inhibition of lipoxygenase activity and leukotrienesynthesis, and in vivo assays for inhibiting bronchoconstriction.

More specifically, a suitable assay for demonstrating inhibition oflipoxygenase activity by the compounds of Formula I utilizeslipoxygenase isolated from mammalian lung tissue, for example, the lungtissue of guinea pigs. An example of such an assay is that described byBen Aziz et al., Anal. Biochem. 34, 88 (1970), incorporated herein byreference. The inhibition of lipoxygenase activity is measured by arapid and sensitive spectrophotometric technique. The compounds ofFormula I of the invention exhibit an IC₅₀ (the concentration at which50% of the enzymatic activity is inhibited) of less than about 100micromoles per liter. Preferred compounds exhibit an IC₅₀ of less thanabout 50 micromoles per liter. Most preferred compounds exhibit an IC₅₀of less than about 10 micromoles per liter.

The activity of the compounds of Formula I may also be demonstrated in amore specific test for leukotriene biosynthesis inhibition. This testutilizes the cell free leukotriene biosynthesis system of M. Steinhoffet al., Biochim. Biophys. Acta. 68, 28 (1980), incorporated herein byreference, which consists of homogenized rat basophil leukemia cells.Leukotriene synthesis is initiated by the addition of arachidonate.Solutions are centrifuged and supernatants assayed using aradioimmunoassay developed as described by Aeringhaus et al., FEBSLetter 146, 111-114, incorporated herein by reference. Drugs aredissolved in ethanol or dimethyl sulfoxide and preincubated for fiveminutes. Phenidone is used as a positive control. The compounds ofFormula I exhibit an IC₅₀ of 100 micromoles per liter or less. Preferredcompounds exhibit an IC₅₀ less than 25 micromoles per liter, and mostpreferred compounds exhibit an IC₅₀ of less than 10 micromoles perliter.

The compounds of Formula I are relatively inactive as inhibitors ofcyclooxygenase. This is important in order for there to be good in vivoantiallergic activity. A convenient in vitro method for measuringcyclooxygenase activity is an assay wherein the amount of thromboxane B₂production is measured in a whole blood clotting assay. The thromboxaneB₂ production is measured by a radioimmunoassay as described by Patrono,et al, Thromb. Res. 17, 317 (1980), incorporated herein by reference.The compounds of Formula I do not show appreciable activity atconcentrations of 100 micromoles per liter.

The in vivo test used to demonstrate anti-allergic activity may be anyof those known to those skilled in the art. Preferably,bronchoconstriction in sensitized guinea pigs is measured upon antigenchallenge. This test is described in broad terms by Piechuta, et al.,Immunology, 38, 385 (1979), incorporated herein by reference, and morespecifically by Hammerbeck and Swingle, Int. Archs. Allergy Appl. Immun.74, 84-90 (1984), incorporated herein by reference. It is used in amodified form as follows: Male Hartley guinea pigs (250-600 g) are dosedwith a compound of Formula I in an amount generally about 1 to 40 mg/kg.Fifteen minutes later the animals are aerosol challenged with eitherwater or ovalbumin at a concentration of 10 mg per ml. The animals arethen placed under an inverted dessicator jar (18×14 cm) with a constantflow of air coming into the chamber from a compressed-air source toprevent hypoxia. Air flow leaving the chamber and fluctuations due torespiration are monitored through a separate outlet with a Fleisch No.0000 pneumotachograph (available from Beckman Instruments, Inc.,Schiller Park, Ill.) coupled to a Beckman Type R dynograph (availablefrom Beckman Instruments). Aerosolization through a third outlet is madevia a No. 40 DeVilbiss nebulizer (available from The DeVilbiss Company,Somerset, Pa.) for 90 seconds at 150 mm Hg. The characteristicrespiratory patterns observed are summations of two air exchangeprocesses occurring simultaneously in the chamber. One exchange processis due to inspiration and expiration of air into and out of the animal,while the other exchange process is due to the air flow into and out ofthe chamber due to respiratory movements. The tracing obtained is themechanical representation of the summation of those flows. Superimposedon the tracings was a characteristic spiking (`notching`), which appearsto be due to an exaggerated expiratory movement, the frequency of whichcorrelates with the severity of the bronchoconstrictive reaction. Thefrequency of notching for 15 minute periods beginning 4 minutes afterthe beginning of the aerosol challenge is used for comparing varioustreatments. Effects are considered significant if the t value achievesp<0.05. Compounds of Formula I exhibit an intraperitoneal ED₄₀ of 100 mgper kg or less when tested in the above model. Preferred compoundsexhibit an ED₄₀ of 20 mg per kg or less. Most preferred compounds of theinvention exhibit an ED₄₀ of 10 mg per kg or less and are effectiveorally.

The imine intermediates of Formula IV are also active as an antiallergicagent and are believed to be reduce in Vivo to the correspondingcompounds of Formula I. Specifically,4-amino-3-(2,6-di-t-butycyclohexadienon-4-ylideneamino)benzoic acid,4-(2,6-ditertiary-butylcyclohexadienon-4-ylideneamino)benzoic acid,4-(2,6-di-tertiarybutylcyclohexadienon-4-ylideneamino)hippuric acid,4-(2,6-ditertiary-butylcyclohexadienon-4-ylideneamino) cinnamic acid,4-acetamido-3-(2,6-di-tertiarybutylcyclohexadienon-4-ylideneamino)benzoicacid, and 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)benzoic acid have been found to exhibit useful activity in the abovedescribed in vivo assay involving bronchoconstriction. The last compoundmentioned above, when administered in vivo to a dog, has been found tobe converted to the compound3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid.

One of the preferred compounds of Formula I of the invention, namely3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid has been found tobe active as a bronchodilator in the small airways of the guinea pig asdetermined using the method described in L. Diamond et al., J. Appl.Physiol.: Respirat. Environ. Exercise Physiol., 43 (6), 942-948 (1977).

Thus, compounds of Formula I are antiallergic agents exhibiting in vivoactivity in mammals. The pharmaceutical compositions of the presentinvention will contain sufficient compound of Formula I in a dosage formsuitable for inhibiting the mammalian biosynthesis of leukotrienes, orfor the treatment desired. The effective concentration of the Formula Icompound in the composition will vary as required by the mode ofadministration, dosage form, and pharmacological effect and leveldesired.

For treating pulmonary conditions such as asthma, the mode ofadministration may be oral, parenteral, by inhalation, by suppositoryand the like. Suitable oral dosage forms are tablets, elixirs,emulsions, solutions, capsules, including delayed or sustained releasedosage forms. Dosage forms for administration by inhalation includeaerosols and sprays which may be administered in metered doses ifdesired.

For treating other allergies or allergic reactions, the compound ofFormula I may be administered by any conventional mode, for example,orally, parenterally, topically, subcutaneously, by inhalation and thelike. The oral and parenteral dosage forms are as described forpulmonary treatment. The topical application dosage forms includeointments, sprays, controlled release patches, powders, solutions andthe like.

For treating inflammation, the mode of administration may be oral,parenteral, by suppository and the like. The various dosage forms are asdescribed above.

For treating skin diseases such as psoriasis, atopic dermatitis and thelike, oral, topical or parenteral administration is useful. For topicalapplication to the diseased area, salves, patches, controlled releasepatches, emulsions, etc. are convenient dosage forms.

For treating cardiovascular conditions any suitable mode ofadministration may be used.

In addition to the common dosage forms listed above, the compounds ofFormula I may also be administered for various utilities and indicationsor for inhibiting leukotriene synthesis by conventional controlledrelease means and/or delivery devices.

In preparing suitable dosage forms, conventional compounding proceduresand ingredients, for example, diluents, carriers, etc. may be used.Examples of suitable solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid,and the like. Examples of suitable liquid carriers are syrup, peanutoil, olive oil, water, and the like. Similarly, the carrier or diluentcan include any time delay material well known to the art, such asglyceryl monostearate or glyceryl distearate, these being useful aloneor, for example, in combination with wax.

The following Examples are provided to illustrate the invention, but arenot intended to limit the invention.

EXAMPLE 1 Preparation of4-(3,5-Di-tertiary-butyl-4-hydroxyanilino)benzoic Acid Step A

A mixture of 22 g (0.10 mole) of 2,6-di(tertiary-butyl)-p-benzoquinone,13.7 g (0.10 mole) of 4-aminobenzoic acid, 175 ml of tetrahydrofuran and1 ml of boron trifluoride: diethyl ether complex was heated on a steambath for 1.25 hours. The mixture was allowed to cool to about 20° C.over 16 hours under a nitrogen atmosphere. Evaporation provided a solidwhich was washed with hexane and recrystallized from ethanol to provideorange solid2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-1-one,m.p. 305°-309° C. Analysis: Calculated for C₂₁ H₂₅ NO₃ : % C, 74.3; % H,7.4; % N, 4.1; Found: % C, 74.2; % H, 7.4; % N, 4.1.

Step B

To a solution of 5.0 g (0.0147 mole) of2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cylohexadien-1-onein 300 ml of ethanol was added 0.25 g of 5 percent palladium oncharcoal. It was subjected to hydrogenation in a Paar apparatus andfiltered. This solvent was removed by evaporation under vacuum and theresidue was recrystallized from a 5:2 (v/v) ethanol-water mixture toprovide light-orange crystals of4-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid, m.p. 241°-243°C. Analysis: Calculated for C₂₁ H₂₇ NO₃ : % C, 73.9; % H, 8.0; % N, 4.1;Found: % C, 73.9; % H 7.9; % N, 3.8/

EXAMPLE 2

Using the method of Example 1, 2,6-di(tertiarybutyl)-p-benzoquinone wasreacted with 3-aminobenzoic acid to provide red-orange crystals of2,6-di(tertiary-butyl)-4-(3'-carboxyphenylimino)-2,5-cyclohexadien-l-one,m.p. 230°-231° C. Analysis: Calculated for C₂₁ H₂₅ NO₃ : % C, 74.3; % H,7.4; % N, 4.1; Found: % C, 74.1; % H, 7.6; % N, 3.7.

EXAMPLES 3-6

Using the general method of Example 1, the aminobenzene startingmaterials of Formula III, shown in Table I below were reacted with2,6-di(tertiary-butyl)-pbenzoquinone to provide the imine productsindicated in Table I.

                                      TABLE I                                     __________________________________________________________________________    Example                                                                            Starting Material Product of Formula IV                                  No.  of Formula III    (m.p. in °C.)                                   __________________________________________________________________________    3    4-aminophenylacetic acid                                                                         ##STR11##                                                   ##STR12##                                                                                       ##STR13##                                             5                                                                                   ##STR14##                                                                                       ##STR15##                                             6                                                                                   ##STR16##                                                                                       ##STR17##                                             __________________________________________________________________________

EXAMPLE 7

To a mixture of 200 ml of ethanol and 23.8 g (0.0701 mole) of2,6-di(tertiary-butyl)-4-(4'-carboxylphenylimino)-2,5-cyclohexadien-1-onewas added 2.9 g (0.072 mole) of sodium hydroxyide in 20 ml of water. Tothis mixture was added 1.0 g to 10% palladium on charcoal, followed bythe addition of 50 ml of water. The mixture was reduced by agitating ona Paar apparatus for about 16 hours. Celite was added to the mixture,and the mixture was filtered through a bed of celite. The mixture wasacidified with 6N hydrochloric acid, and the resulting yellow solidprecipitate was collected by filtration to provide4-[3,5-di(tertiary-butyl)-4-hydroxyanilino]benzoic acid, m.p. 241°-242°C.

EXAMPLE 8

To a mixture of 200 ml of ethanol and 25.0 g (0.0736 mole) of2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-l-oneand 12 g (0.087 mole) of potassium carbonate warmed on a steam bath wasadded 1.0 g of palladium on charcoal. The mixture was reduced using aPaar apparatus for 2 hours. The mixture was diluted with 300 ml ofwater, filtered through celite, and the filtrate acidified with 6Nhydrochloric acid. The yellow solid precipitate was collected byfiltration to provide 4-[3,5-di(tertiary-butyl)-4-hydroxyanilino]benzoicacid, m.p. 241°-242° C.

EXAMPLES 9-13

Using the general method of Example 7 or 8 the imine intermediatesobtained in Example 2-6 were reduced to provide compounds of Formula Ishown in Table II below:

                                      TABLE II                                    __________________________________________________________________________    Example                                                                            Intermediate of                   Melting Point                                                                        Hydrogenation                   No.  of Formula IV                                                                         Product of Formula I      in °C.                                                                        Method used                     __________________________________________________________________________     9   Example 3                                                                              ##STR18##                186-188                                                                              Example 8                       10   Example 4                                                                              ##STR19##                202.5-203.5                                                                          Example 7                       11   Example 5                                                                              ##STR20##                177.5-178                                                                            Example 7                       12   Example 6                                                                              ##STR21##                239.5-240                                                                            Example 7                       13   Example 2                                                                              ##STR22##                250.5-252                                                                            Example 7                       __________________________________________________________________________

EXAMPLE 14

A mixture of a solution of 6.3 g (0.018 mole) of4-[3,5-di-(tertiary-butyl)-4-hydroxyanilino]phenylacetic acid in 10 mlof N,N-dimethylformamide and 5 g (0.036 mole) of potassium carbonate washeated on a steam bath until gas evolution ceased. The mixture wasallowed to cool to ambient temperature, and 5 milliliters of methyliodide were then added. The mixture was heated at its boilingtemperature and 5 ml aliquots of methyl iodide were added at 20, 45 and60 minutes. After the mixture had evaporated, the residue was taken upin water and 2N sodium hydroxide solution was added. The mixture waswarmed, and the insoluble residue of methyl4-[3,5-di(tertiary-butyl)-4-hydroxy-N-methyl-anilino]phenylacetate wasseparated by filtration. The residue was suspended and partiallydissolved in 50 ml of methanol, and 10 ml of 2.5N sodium hydroxidesolution was added. The mixture was stirred for about 16 hours, dilutedwith 300 ml of water and 300 ml of diethyl ether, and was then furtherdiluted with about 100 ml of hexane. The mixture was acidified withdilute hydrochloric acid and the aqueous phase was discarded. Theorganic phase was washed first with 10% sodium bicarbonate solution andthen with 5% sodium carbonate solution. The product remained in theorganic phase as the sodium salt. The organic phase was acidified with10% aqueous hydrochloric acid and washed with sodium chloride solution,followed by drying. Evaporation provided a residue which was extractedwith 20 ml of boiling benzene. Hexane (6 ml) was added, and the lightyellow solid was recrystallized first from 80% aqueous ethanol, and thenfrom benzene to provide fine yellow needles of4-[3,5-di(tertiary-butyl)-4-hydroxy-N-methylanilino]phenylacetic acid,m.p. 181°-182.5° C. Analysis: Calculated for C₂₃ H₃₁ NO₃ ; % C, 74.8; %H, 8.5; % N, 3.8; Found: % C, 74.8; % H, 8.6; % N, 3.6.

EXAMPLE 15

A solution of 3.4 g (0.010 mole) of4-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid (prepared inExample 1) in 35 ml of N,N-dimethylformamide and 3.5 ml of methyl iodidewas heated at 95° C. for about 48 hours under nitrogen. The reactionmixture was poured into cold water and the resulting solid was collectedand then taken up in chloroform. The chloroform solution was filtered,washed with water, dried with magnesium sulfate and evaporated to give atan solid. This material was recrystallized first from benzene and thenfrom a mixture of ethanol and water to give 1.5 g of white crystalline4-(3,5-di-tertiary-butyl-4-hydroxy-N-methylanilino)benzoic acid, m.p.240°-244° C. Analysis: Calculated for C₂₂ H₂₉ NO₃ : % C, 74.3; % H, 8.2;% N, 3.9. Found: % C, 74.4; % H, 8.3; % N, 3.5.

EXAMPLE 16

A mixture of 2.0 g (0.00589 mole) of2,6-di(tertiary-butyl)-4-(4-carboxyphenylimino)-2,5-cyclohexadien-1-oneand 2.5 g of sodium thiosulfite in 25 ml of 1N sodium hydroxide solutionand a few ml of diethyl ether were stirred at 20° C. After one hour ofstirring the mixture was heated on a steam bath while adding 1.5 g ofsodium thiosulfite and enough sodium hydroxide to make the solutionalkaline. After one hour the solution was acidified with 6N hydrochloricacid. The precipitate separated by filtration to provide a light orangesolid was about 50% 3-[3,5-di(tertiary-butyl)-4-hydroxyanilino]benzoicacid according to thin layer chromatographic and infrared spectralanalyses.

EXAMPLES 17-19

Using the general method of Example 1, the aminobenzene startingmaterials of Formula III below were reacted with2,6-di(tertiary-butyl)-p-benzoquinone to provide the imine productsindicated in TABLE III.

                                      TABLE III                                   __________________________________________________________________________         Starting    Product of         Melting                                   Example                                                                            Material of Formula IV         Point                                     Number                                                                             Formula III (m.p. in ° C.                                                                             in °C.                             __________________________________________________________________________    17                                                                                  ##STR23##                                                                                 ##STR24##         (241-245)                                 18                                                                                  ##STR25##                                                                                 ##STR26##         (249-259)                                 19                                                                                  ##STR27##                                                                                 ##STR28##         (195-199)                                 __________________________________________________________________________

EXAMPLE 20

To a mixture of 225 ml ethanol and 13.6 g (0.038 mole) of2,6-di(tertiary-butyl)-4-(5'-carboxy-2'-methylphenylimino)-2,5-cyclohexadiene-1-one(from Example 18) was added 1 g of 5% palladium on charcoal (50% waterwet). The mixture was reduced by agitating on a Paar apparatus for 2hours. The mixture was filtered through celite to remove the catalystand the filtrate was concentrated on a rotary evaporator to give 13.0 gof a light orange solid, m.p. 229°-233° C. This material wasrecrystallized from aqueous ethanol to give 10.8 g orange crystallinesolid m.p. 234°-239° C. This material was in turn recrystallized frombenzene to give 9.6 g pale orange solid3-(3,5-di-tertiary-butyl-4-hydroxyanilino)-4-methylbenzoic acid, m.p.234°-239° C. Analysis: Calculated for C₂₂ H₂₉ NO₃ : % C 74.3; % H 8.2, %N 3.9 Found: % C, 74.3; % H, 8.2; % N 3.8.

EXAMPLE 21-22

Using the general method of Example 20, the imine intermediates obtainedin Examples 18 and 19 were reduced to provide compounds of Formula Ishown in TABLE IV below:

                  TABLE IV                                                        ______________________________________                                        Example                                                                       Number   Product of Formula I (m.p. in °C.)                            ______________________________________                                        21                                                                                      ##STR29##                                                           22                                                                                      ##STR30##                                                           ______________________________________                                    

EXAMPLE 23

A mixture of 22.0 g (0.10 mole) of2,6-di(tertiary-butyl)-p-benzoquinone, 19.0 g (0.105 mole) of(4-aminophenyl)thioacetic acid, 100 ml of tetrahydrofuran and 1 ml ofboron trifluoride: diethyl ether complex was heated at gentle reflux,with stirring, for 1.5 hours. The reaction mixture was concentratedunder a nitrogen gas flow to a volume of 75 ml. The concentrate wasdiluted with 250 ml ethanol and 1 g of palladium on charcoal was added.This mixture was hydrogenated on a Paar apparatus for 12 hours, thenfiltered through celite to remove the catalyst. The filtrate wasconcentrated to give 33.7 g of an oil. The oil was taken up in diethylether. This solution was washed with dilute (about 10%) hydrochloricacid, then dried and evaporated to give 18.4 g of a gummy solid. Thismaterial was recrystallized from 5:6 benzene:hexane to give 6.3 g ofpink solid 4-(3,5-di-tertiary-butyl-4-hydroxyanilino)phenylthioaceticacid, m.p. 136.5°-137.5° C. Analysis: Calculated for C₂₂ H₂₉ NO₃ S: % C,68.2; % H, 7.5; % N, 3.6. Found: % C, 68.3; % H, 7.7; % N, 3.3.

EXAMPLE 24

A mixture of 22.5 g (0.105 mole) of2,6-di-tertiary-butyl-p-benzoquinone, 11.8 g (0.10 mole) ofanthranilonitrile, 50 ml of tetrahydrofuran and 1 ml of borontrifluoride:diethyl ether complex was heated at gentle reflux for 2hours. Heating was continued for an additional 2 hours under a stream ofnitrogen gas to concentrate the mixture. The concentrated mixture wasdiluted with 50 ml of ethanol, warmed to effect complete dissolution,and then allowed to cool. The precipitate was collected, rinsed withcold 4:1 methanol:water, and oven dried to give 23.6 g of orangecrystals of2,6-di-tertiary-butyl-4-(2'-cyanophenylimino)-2,5-cyclohexadien-1-one,m.p. 109°-110.5° C.

To a mixture of 15.0 g (0.0468 mole) of2,6-di-tertiary-butyl-4-(2'-cyanophenylimino)-2,5-cyclohexadien-1-one(obtained above) and 200 ml of ethanol was added 1 g of palladium oncharcoal. The mixture was hydrogenated on a Paar apparatus for 10minutes. The solvent was decanted off, then the residual solid wasdissolved in chloroform. The chloroform solution was mixed with ethanol,filtered, and concentrated to give 14.6 g of tan solid, m.p. 170°-173°C. A portion (1.9 g) of this material was recrystallized from ethanol togive pale orange prisms of the novel compound2-(3,5-di-tertiarybutyl-4-hydroxyanilino)benzonitrile, m.p.171.5°-172.5° C. Analysis: Calculated for C₂₁ H₂₆ N₂ O: % C 78.2; % H8.1; % N 8.7. Found: % C 78.3; % H 8.3; % N 8.6.

A mixture of 5.8 g (0.018 mole)2-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzonitrile, 40 g of 50%sodium hydroxide and 100 ml of ethanol was heated at gentle reflux for 3hours. The reaction mixture was poured onto a mixture of 100 ml of 6Nhydrochloric acid and ice. The precipitate was collected and dried in avacuum oven to give 5.8 g of yellow solid, m.p. 217°-219° C. Thismaterial was recrystallized from a mixture of ethanol and water to give4.9 g of light orange needles ofN-(3,5-di-tertiarybutyl-4-hydroxyphenyl)anthranilic acid, m.p.220.5°-221.5° C. Analysis: Calculated for C₂₁ H₂₇ NO₃ : % C 73.9; % H8.0; % N 4.1; Found: % C 74.1; % H 8.1; % N 4.0.

EXAMPLES 25-26

Using the general method of Example 1 the starting materials of FormulaVI shown in TABLE V below were reacted with2,6-di(tertiary-butyl)-p-benzoquinone to provide the imine productsindicated in TABLE V.

    ______________________________________                                               Starting                                                               Example                                                                              Material of    Product of Formula I                                    Number Formula VI     (m.p. in °C.)                                    ______________________________________                                        25                                                                                    ##STR31##                                                                                    ##STR32##                                              26                                                                                    ##STR33##                                                                                    ##STR34##                                              ______________________________________                                    

EXAMPLE 27

Using the method of Example 20, 8.0 g of2,6-di-t-butyl-4-(3'-cyanophenylimino)-2,5-cyclohexadien-1-one (fromExample 26) was converted to3-(3,5-di-t-butyl-4-hydroxyanilino)benzonitrile, m.p. 150°-153° C.

EXAMPLE 28

Eight g (0.025 mole) of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzonitrile(from Example 27), 4.9 g (0.075 mole) of sodium azide, 4.0 g (0.075mole) of ammonium chloride, 1.06 g (0.025 mole) of lithium chloride and60 ml of N,N-dimethylformamide were combined under a nitrogen atmosphereand heated at 110° C. for 48 hours. The reaction mixture was poured intocold 6N hydrochloric acid and a gummy solid precipitated out. Thesupernatant was decanted off and the residue dissolved in ethanol. Theethanol solution was diluted with water and a pink solid was collected.This material was recrystallized from a mixture of ethanol and water togive 5.97 g of 5-[3-(3,5-di-t-butyl-4-hydroxyanilino)phenyl]tetrazole,m.p. 231°-233° C. Analysis: Calculated for C₂₁ H₂₇ N₅ O: % C, 69.0; % H,7.4; % N, 19.2; Found: % C, 68.4; % H 7.6; % N 18.8.

EXAMPLE 29

Using the method of Example. 20, 10 g of2,6-di-t-butyl-4-(4'-cyanophenylimino-2,5-cyclohexadien-1-one (fromExample 27) was hydrogenated to give4-(3,5-di-t-butyl-4-hydroxyanilino)benzonitrile.

EXAMPLE 30

Seven g (0.0205 mole) of 4-(3,5-di-t-butyl-4-hydroxyanilino)benzonitrile(from Example 29), 4.01 g (0.0615 mole) of sodium azide, 3.29 g (0.0615mole) of ammonium chloride and 50 ml of N,N-dimethylformamide werecombined and heated first at 105° C. for 20 hours and then at 150° C.for 9 hours. The reaction mixture was diluted with diethyl ether andwater and acidified with 6N HCl. The ether phase was washed with sodiumchloride solution, dried over sodium sulfate, and concentrated to an oilunder a stream of nitrogen. The crude product was treated withchloroform and hexane to convert it from an oil to a solid. The solidwas recrystallized from a mixture of ethanol and water to give 2.6 g oflight orange needles of5-[4-(3,5-di-t-butyl-4-hydroxyanilino)phenyl]tetrazole, m.p. 224°-225°C. Analysis: Calculated for C₂₁ H₂₇ N₅ O.C₂ H₅ OH: % C, 67.1; % H, 8.1;% N, 17.0; Found: % C, 67.1; % H, 8.2; % N, 16.9.

EXAMPLE 31

Preparation of N,N-Dimethyl-2-aminoethyl3-(3,5-Di-tertiary-butyl-4-hydroxyanilino)benzoate.

Under a nitrogen atmosphere, 6.0 g (0.0176 mole) of3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid (from Example 13)and 2.53 g (0.0176 mole) of 2-dimethylaminoethyl chloride hydrochloridewere dissolved in 17 ml of N,N-dimethylformamide. To this mixture wasadded 4.9 ml (0.035 mole) of triethylamine and the reaction was heatedat 100° C. for 25 hours. The reaction temperature was then raised to120° C. and heating was continued for an additional 28 hours. Thereaction mixture was diluted with 10 ml of diethyl ether, then filteredto remove triethylamine hydrochloride. The filtrate was diluted withadditional diethyl ether and then shaken with cold 10% hydrochloricacid. A middle layer contained most of the product hydrochloride. It wasdiluted with water and ether, and basified with solid sodium carbonate.The ether extract was washed with saturated aqueous sodium chloride andthen concentrated to give 1.7 g of a tan solid, m.p. 119°-120° C. Thismaterial was recrystallized first from 20 ml of cyclohexane and thenfrom a mixture of 10 ml of ethanol and 3 ml of water to give 1.48 g oflight yellow prisms of N,N-dimethyl-2-aminoethyl3-(3,5-di-t-butyl-4-hydroxyanilino)benzoate m.p. 123°-124° C. Analysis:Calculated for C₂₅ H₃₆ N₂ O₃ : % C, 72.8; % H, 8.8; % N, 6.8. Found: %C, 73.0; % H, 8.8; % N, 6.7.

EXAMPLE 32

Preparation of N-Acetyl-3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic Acid.

A mixture of 5.6 g of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid(from Example 13) and 15 ml of acetic anhydride was heated under anitrogen atmosphere at 70°-120° C. for about 90 minutes. The mixture wascooled to 80° C., 5 drops of pyridine were added and the reaction wasreheated to 120° C. for 10 minutes. An additional 0.25 ml of pyridinewas added at about 80° C., followed by the gradual addition of 10 ml ofwater to hydrolyze the excess acetic anhydride and the mixed anhydrideof the product. Heating was continued until a precipitate formed. Thereaction mixture was allowed to cool to room temperature, and theprecipitate was then collected, rinsed with a cold mixture of methanoland water, and dried to give 4.3 g of off-white solid m.p. 204°-205.5°C. This material was recrystallized first from a mixture of 30 ml ofethanol and 5 ml of water, and then from a mixture of 30 ml ofisopropanol and 5 ml of hexane to give 3.3 g of white solidN-acetyl-3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid m.p.214.5°-215.5° C. Analysis: Calculated for: C₂₃ H₂₉ NO₄.1/2(CH₃)₂ CHOH: %C, 71.2; % H, 8.0; % N 3.4. Found: % C, 71.4; % H, 8.1; % N, 3.2.

EXAMPLE 33

Preparation ofN-Trifluoroacetyl-3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic Acid.

2.96 g of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid (from Example13) was slurried in 10 ml of trifluoroacetic anhydride. After severalminutes, the reaction boiled (40° C.) and then became clear. Thereaction mixture was poured into a mixture of ice and water and theresulting solid was collected and dried. This material wasrecrystallized from a mixture of 40 ml of ethanol and 12 ml of water togive 3.07 g of white crystallineN-trifluoroacetyl-3-(3,5-di-t-butyl-4-hydroxyanilino)-benzoic acid m.p.181° C. Analysis: Calculated for C₂₃ H₂₆ F₃ NO₄ : % C, 63.1; % H, 6.0; %N, 3.2. Found: % C, 63.0; % H, 6.4; % N, 2.8.

EXAMPLE 34

A mixture of 22.0 g (0.10 mole) of 2,6-di-t-butyl-p-benzoquinone, 15.2 g(0.10 mole) of 3,4-diaminobenzoic acid, 50 ml of tetrahydrofuran and 1ml of boron trifluoride etherate was heated at about 55° C. for 45minutes. The reaction mixture was diluted with 100 ml of ethanol and 40ml of water and was then allowed to stand overnight at 25° C. Theresulting precipitate was collected and dried to give 31.8 g of deep redsolid 4-amino-3-(3,5-di-t-butylcyclohexadienon-4-ylideneamino)benzoicacid, m.p. 253°-253.5° C. Analysis: Calculated for C₂₁ H₂₆ N₂ O₃ : % C,71.2; % H, 7.4, % N, 7.9. Found: % C, 71.0; % H, 7.5; % N, 7.8.

A mixture of 21.1 g of4-amino-3-(3,5-di-t-butylcyclohexadienon-4-ylideneamino)- benzoic acid,50 ml of ethanol, 20 ml of water, 2.4 g of sodium hydroxide and 0.03 gof 5% palladium on charcoal catalyst was placed on a Paar apparatus.After 16 hours the hydrogen uptake was complete. Under a nitrogenatmosphere, the reaction was filtered into 13 ml of 6N hydrochloricacid. The filtrate was diluted with water and additional hydrochloricacid. The resulting precipitate was collected, rinsed with a coldmixture of methanol and water and dried to give 15.5 g of a lavendersolid, m.p. 261.5°-262° C. Two g of this material was stirred with 150ml of warm ethyl acetate, and was then filtered. The filtrate wasdiluted with 25 ml of hexane. The resulting precipitate was collectedand dried to give 0.3 g of light purple crystalline4-amino-3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid m.p. 261°-261.5°C. Analysis: Calculated for C₂₁ H₂₈ N₂ O₃ : % C, 70.8; % H, 7.9; % N,7.9. Found: % C, 70.8; % H, 7.9; % N, 7.6.

EXAMPLE 35

Under a nitrogen atmosphere, a suspension of 2.0 g of5-[4-(3,5-di-tertiary-butyl-4-hydroxyanilino)phenyl]tetrazole, preparedin Example 30, and 2.0 g of potassium carbonate in 4 ml ofN,N-dimethylformamide was warmed to obtain a deep red solution of thepotassium salt. Approximately 4 g of methyl iodide was added and thereaction was warmed for several minutes until the color lightened. Anadditional 4 g of methyl iodide was added and the reaction mixture washeated at a gentle reflux for about five minutes. The reaction mixturewas cooled, diluted with diethyl ether, and poured into dilutehydrochloric acid. The ether phase was washed with water and brine,dried with sodium sulfate, and evaporated to give 1.88 g of a red-brownsolid. This material was recrystallized from a mixture of benzene andhexane to give 0.53 g of light yellow-tan Material #1, m.p. about 205°C. A solid precipitated from the mother liquor of Material #1. It wascollected to give 0.73 g of pink Material #2, m.p. 172°-175.5° C.Material #1 was recrystallized from a mixture of 20 ml of ethanol and 5ml of water to give 0.34 g of light brown granules, m.p. 218°-221° C.Material #2 was stirred with 50 ml of ethanol, then filtered to removesome undissolved material. The filtrate was diluted with 20 ml of waterto give 0.56 g of pale pink leaflets, m.p. 175.5°-177° C. By proton NMRanalysis, Material #1 is believed to be the 1-methyltetrazole andMaterial #2 the 2-methyltetrazole. The delta-values are 4.15 and 4.36ppm, respectively, for the two products.

EXAMPLE 36

Using the method of Example 1, 4-aminobenzylcyanide was reacted with2,6-di-tertiary-butyl-p-benzoquinone to give2,6-di-tertiary-butyl-4-(4'-cyanomethylphenylimino)-2,5-cyclohexadiene-1-one,m.p. 126.5°-127.5° C. Following the reduction method of Example 1, StepB, the corresponding anilino phenylacetonitrile, m.p. 146°-147° C., wasobtained. This was converted to5-[4-(3,5-di-t-butyl-4-hydroxyanilino)benzyl]tetrazole, m.p. 212°-214°C. (dec), following the method of Example 30, but carried out at 110° C.for 48 hours.

EXAMPLE 37

Example 36 was rerun using tin tetrachloride instead of borontrifluoride as the catalyst. Thin layer chromatography using twodifferent systems showed that the reaction mixture contained the desired2,6-di-tertiarybutyl-4-(4'-cyanomethylphenylimino)-2,5-cyclohexadien-1-one

EXAMPLE 38

Example 36 was rerun using titanium tetrachloride instead of borontrifluoride as the catalyst. Thin layer chromatography using twodifferent systems showed that the reaction mixture contained the desired2,6-di-tertiarybutyl-4-(4'-cyanomethylphenylimino)-2,5-cyclohexadiene-1-one.

EXAMPLE 39

A mixture of 1.70 g (0.005 mole) of3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid (prepared inExample 13) and 50 ml of hot isopropyl alcohol was filtered to remove asmall amount of insoluble material. The resulting solution wasdeoxygenated with a stream of nitrogen gas. Under a nitrogen atmosphere,a solution of 0.44 g (0.005 mole) of morpholine in 1.5 ml of isopropylalcohol was added with rapid stirring. Evaporation provided a solidwhich was recrystallized from a mixture of isopropyl alcohol andisopropyl ether to give solidmorpholinium-3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoate, m.p.147°-150° C. Analysis: Calculated for C₂₁ H₂₇ NO₃ C₄ H₉ NO: % C, 70.1; %H, 8.5; % N, 6.5; Found: % C, 69.8; % H, 8.5; % N, 6.4.

EXAMPLE 40

A suspension of 6.68 g (0.0196 mole) of2,6-di-tertiary-butyl-4-(3'-carboxyphenylimino)-2,5-cyclohexadien-1-one(prepared in Example 2) in 20 ml of benzene and 3 ml of thionyl chloridewas heated at reflux with stirring until gas evolution had ceased.Evaporation provided an oil which was diluted with a small amount oftetrahydrofuran and added dropwise to a suspension of 3.7 g of anhydrous5-aminotetrazole in 25 ml of tetrahydrofuran containing 1.5 ml ofpyridine. The reaction mixture was allowed to stand at room temperatureunder a nitrogen atmosphere for 16 hours. The reaction mixture wasdiluted to a volume of 500 ml with diethyl ether, and was then filtered.The filter cake was rinsed with diethyl ether and resuspended in 300 mlof diethyl ether and filtered again. The combined filtrates wereevaporated to give 4.7 g of an orange solid, m.p. 241°-244° C. One g ofthis material was recrystallized from ethanol to provide 0.3 g of orange3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)-N-(5-tetrazolyl)benzamide,m.p. 271.5° C. (dec.). Analysis: Calculated for C₂₂ H₂₆ N₆ O₂ : % C,65.0; % H, 6.4; % N, 20.7; Found: % C, 65.1; % H, 6.4; % N, 20.5.

A of mixture of 3.1 g3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)-N-(5-tetrazolyl)benzamide,200 ml of tetrahydrofuran, and 0.7 g of palladium on charcoal catalystwas placed on a Paar apparatus. Hydrogenation was complete after twohours. Under a nitrogen atmosphere, the reaction was filtered to removethe catalyst. The filtrate was evaporated to give 4.3 g of a stickyyellow solid which was recrystallied from a mixture of 130 ml aceticacid and 20 ml of water to give 1.6 g of yellow solid3-(3,5-di-tertiary-butyl-4-hydroxyanilino)-N¹ -(5-tetrazolyl)benzamide,m.p. 282°-283° C. Analysis: Calculated for C₂₂ H₂₈ N₆ O₂ : % C, 64.7; %H, 6.9; % N, 20.6; Found: % C, 64.6; % H, 6.8; % N, 20.2.

EXAMPLE 41

A mixture of 5.51 g (0. 025 mole ) of2,6-di-tertiary-butyl-p-benzoquinone, 4.54 g (0.027 mole) of3-(4-aminophenyl)propionic acid, 50 ml of tetrahydrofuran and 0.25 ml ofboron trifluoride etherate was heated on a steam cone under a slowstream of nitrogen for two hours. The resulting solid was trituratedwith hexane, collected, rinsed with hexane and recrystallized from amixture of ethyl acetate and hexane to give 5.1 g yellow3-[4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenyl]propionicacid, m.p. 165°-167° C. Analysis: Calculated for C₂₃ H₂₉ NO₃ : % C,75.2; % H, 8.0; % N, 3.8; Found % C, 74.8; % H, 7.9; % N, 3.7.

A mixture of 4.0 g of3-[4-(2,6-di-tertiarybutylcyclohexadienon-4-ylideneamino)phenyl]propionicacid, 200 ml of ethanol of 0.1 g of 10% palladium on charcoal catalystwas placed on a Paar apparatus. Hydrogen uptake was complete after 30minutes. Under a nitrogen atmosphere, the reaction mixture was filteredto remove catalyst. The filtrate was evaporated to give an oil which wascoevaporated with hexane to remove all traces of ethanol and thentriturated with hexane to give a light orange crystalline solid. Thissolid was recrystallized from a mixture of ethanol and water to give 3.1g 3-[N-(3,5-di-tertiary-butyl-4-hydroxyphenyl)-4-aminophenyl]propionicacid, m.p. 140°-142° C. Analysis: Calculated for C₂₃ H₃₁ NO₃ : % C,74.8; % H, 8.5; % N, 3.8; Found: % C, 74.7; % H, 8.3; % N, 3.9.

EXAMPLE 42

A mixture of 22.0 g (0.10 mole) of 2,6-di-tertiary-butyl-p-benzoquinone,10.9 g (0.01 mole) of m-aminophenol, 50 ml of tetrahydrofuran and 0.5 mlof boron trifluoride etherate was stirred at room temperature for aboutone hour. The reaction mixture was diluted with diethyl ether, and theether solution was extracted with 10% hydrochloric acid and dried overmagnesium sulfate. Evaporation gave an orange-red solid. This materialwas dissolved in a mixture of diethyl ether and methylene chloride. Thesolution was filtered, and was then evaporated to give 29.1 g orange-redsolid. This material was recrystallized from a mixture of 50 ml ofbenzene and 100 ml of hexane to give 17.0 g of orange-red crystals, m.p.162°-169° C. This material (2.5 g) was recrystallized first from amixture of 15 ml benzene and 10 ml of hexane and then from a mixture of10 ml of isopropanol and 7 ml of water to give 1.3 g of orangecrystalline3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenol, m.p.169°-169.5° C. Analysis: Calculated for C₂₀ H₂₅ NO₂ : % C, 77.1; % H,8.1; % H, 4.5; Found: % C, 77.2; % H, 8.0; % N, 4.6.

1.36 g (0.027 mole) of 50% sodium hydride was added in portions to asolution of 7.06 g (0.023 mole) of3-(2,6-di-tertiary-butylcyclohexadienon-4-ylidenamino)phenol in amixture of 50 ml 1,2-dimethoxyethane and 10 ml of dimethylacetamide.Three ml (0.027 mole) of ethyl bromoacetate was then added in portions.The reaction mixture was stirred at room temperature for about one hour,and a solution of 1.3 g of sodium hydroxide in 12 ml of water was added.After about 30 minutes the reaction mixture was acidified withhydrochloric acid and was extracted with diethyl ether. The etherextract was washed with a saturated sodium chloride solution andevaporated to give an orange solid. This solid was recrystallized from amixture of benzene and hexane to give 6.2 g of an orange solid, m.p.161°-162° C. One g of this material was recrystallized from a mixture of10 ml of ethanol and 5 ml of water to give 0.8 g of orange crystalline3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenoxyaceticacid, m.p. 163°-165° C. Analysis: Calculated for C₂₂ H₂₇ NO₄ : % C,71.5; % H, 7.4; % N, 3.8; Found: % C, 71.8; % H, 7.2; % N, 3.7.

A mixture of 5.0 g of3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenoxyaceticacid, 250 ml of ethanol and 10 mg of 5% palladium on charcoal catalystwas placed on a Paar apparatus. Hydrogenation was complete after fivehours. The reaction mixture was filtered to remove the catalyst and thefiltrate was evaporated to give a thick brown oil. The oil was dissolvedin 20 ml of benzene, filtered, diluted with 20 ml of cyclohexane and 10ml of hexane, and chilled to give 1.4 g of light tan crystalline3-(3,5-di-tertiary-butyl-4-hydroxyanilino)phenoxyacetic acid, m.p.127°-127.5° C. Analysis: Calculated for C₂₂ H₂₉ NO₄ : % C, 71.1; % H,7.9; % N, 3.8; Found: % C, 70.3; % H, 7.6; % N, 3.7.

EXAMPLE 43

A suspension of 6.0 g (0.027 mole) of2,6-di-tertiary-butyl-p-benzoquinone, 3.3 g (0.020 mole) ofp-aminocinnamic acid, 15 ml of tetrahydrofuran and 0.3 ml of borontrifluoride etherate was heated at reflux for one hour. The reactionmixture was dissolved in a minimum amount of methylene chloride, and wasdiluted to a final volume of 700 ml with diethyl ether. The ethersolution was washed first with cold 10% hydrochloric acid and then withbrine, and was then dried over magnesium sulfate and evaporated almostto dryness. The residue was diluted with 300 ml of hexane and evaporatedalmost to dryness before being diluted with 500 ml of warm hexane. Themixture was allowed to cool to room temperature before being filtered togive 5.8 g of a bright red powder. One g of this material wasrecrystallized from a mixture of 15 ml of benzene and 3 ml of hexane togive 0.5 g of red crystalline4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)cinnamic acid,m.p. 216°- 217.5° C. Analysis: Calculated for C₂₃ H₂₇ NO₃ : % C, 75.6; %H, 7.4; % N, 3.8; Found: % C, 75.9; % H, 7.5; % N, 3.8.

A mixture of 2.0 g of4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)cinnamic acid,100 ml of methanol, 0.5 ml of concentrated hydrochloric acid and 2 g ofzinc powder was stirred for ten minutes. The mixture was filtered andthe filtrate was evaporated to give a yellow gummy solid. This materialwas recrystallized from a mixture of 15 ml of benzene, 4 ml of hexaneand 2 ml of cyclohexane to give 0.4 g of yellow granular4-(3,5-di-tertiary-butyl-4-hydroxyanilino)cinnamic acid, m.p. 199°-200°C. Analysis: Calculated for C₂₃ H₂₉ NO_(32/3) C₆ H₆ : % C, 77.4; % H,7.9; % N, 3.3; Found: % C, 77.2; % H, 7.8; % N, 3.3.

EXAMPLE 44

A suspension of 5.0 g (0.0147 mole) of2,6-di-tertiary-butyl-4-(3'-carboxyphenylimino)-2,5-cyclohexadien-1-one(prepared in Example 2) in 15 ml of benzene and 2.5 ml of thionylchloride was heated at reflux until gas evolution ceased. The solutionwas evaporated, and was evaporated twice more following additions ofbenzene. The resulting acid chloride was added dropwise to a solution of5.5 g sodium trifluoromethanesulfonamide in 25 ml of1,2-dimethoxyethane. The solvent was evaporated with a stream ofnitrogen to give a yellow solid. This solid was stirred with 200 ml oftetrahydrofuran and was then filtered to remove insoluble material. Thefiltrate was hydrogenated for 16 hours on a Paar apparatus using 0.5 gof 5% palladium on charcoal as the catalyst. The catalyst was removed byfiltration and the filtrate was evaporated to give a dark brown oil. Theoil was dissolved in 25 ml of water. This solution was added to amixture of 5.0 ml of 10% hydrochloric acid, water and ice to give 6.7 gof a white solid. This solid was recrystallized from a mixture of 70 mlof ethanol and 20 ml of water to give 3 g of white crystallineN-[3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoyl]trifluoromethanesulfonamide,m.p. 234°-234.5° C. Analysis: Calculated for C₂₂ H₂₇ F3N₂ O₄ S: % C,55.9; % H, 5.8; % N, 5.9; Found: % C, 56.1; % H, 5.8; % N, 5.9.

EXAMPLE 45

A mixture of 13.2 g (0.10 mole) of 3-amino-4-hydroxybenzoic acid, 22.0 g(0.10 mole) of 2,6-di-tertiary-butyl-p-benzoquinone, 25 ml oftetrahydrofuran and 1 ml of boron trifluoride etherate was heated at agentle reflux for about 20 minutes by which time a thick precipitate hadformed. The reaction mixture was diluted with 50 ml of ethanol andfiltered to obtain 20.9 g of an orange solid, m.p. 248°-250° C. Six g ofthis material was recrystallized from a mixture of 250 ml of ethanol and70 ml of water to give 3.4 g of red granular3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)-4-hydroxybenzoicacid, m.p. 275°-276° C. Analysis: Calculated for C₂₁ H₂₅ NO₄ : % C,71.0; % H, 7.1; % N, 4.0; Found: % C, 71.4; % H, 7.1; % N, 3.8.

A mixture of 5.0 g of3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)-4-hydroxybenzoicacid, 0.05 g of 5% palladium on charcoal catalyst, 250 ml of ethanol and50 ml of tetrahydrofuran was placed on a Paar apparatus. Hydrogen uptakewas complete in about 10 minutes. The reaction mixture was filtered toremove catalyst. The filtrate was evaporated to give a tan solid whichwas recrystallized from a mixture of 40 ml of ethanol and 15 ml of waterto give 3.2 g of reddish tan granular3-(3,5-di-tertiary-butyl-4-hydroxyanilino)-4-hydroxybenzoic acid, m.p.254.5°-255° C. (dec). Analysis: Calculated for C₂₁ H₂₇ NO₄ : % C, 70.6;% H, 7.6; % N, 3.9; Found: % C, 71.0; % H, 7.6; % N, 4.1.

What is claimed is:
 1. A compound of the formula ##STR35## wherein R ishydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, amino,lower alkylamino, di(lower alkylamino), lower acylamido, or hydroxy, andn is 0, 1 or 2, with the proviso that if n is 2, all R substituentscombined contain no more than 6 carbon atoms; R' is hydrogen, loweralkyl, acetyl or trifluoroacetyl; A is carboxyl or ##STR36## and when Ais carboxyl, B is a carbon-carbon bond, lower alkylene, loweralkenylene, lower alkylene containing one ether or thioether link in thealkylene chain, or ##STR37## and when A is ##STR38## B is acarbon-carbon bond; or a derivative of a compound wherein A is carboxyl,said derivative selected from the group consisting of a lower alkylester, a (lower)alkylamino(lower)alkyl ester, a pharmaceuticallyacceptable (lower) alkylamino(lower)alkyl ester acid-addition salt, anda pharmaceutically acceptable carboxylate salt.
 2. A compound accordingto claim 1, wherein A is carboxyl.
 3. A compound according to claim 2,wherein B is a carbon-carbon bond or methylene.
 4. A compound accordingto claim 1 wherein R is hydrogen.
 5. A compound according to claim 1,wherein --B--A is oriented meta or para to the ##STR39## linking.
 6. Acompound according to claim 1, wherein B is a carbon-carbon bond.
 7. Apharmaceutical anti-allergic composition comprising a compound accordingto claim 1 and a pharmaceutically acceptable vehicle, said compoundbeing present in an amount effective for providing an anti-allergicresponse.